Impaired wound healing is a significant clinical problem, and affects approximately 6.5 million people in the United States. One tissue that nearly always heals exceptionally quickly is the mucosa of the oral cavity. While skin and oral mucosa share many morphological similarities, oral mucosal wounds heal more rapidly and display less inflammation and scar formation than skin wounds. Epithelial cells from oral mucosa exhibit increased migratory and proliferative capacities when compared to cells from skin, suggesting that the improved repair of mucosa may involve intrinsic differences in epithelial cells. While a few laboratories (including our group) have started to investigate the molecular mechanisms that contribute to this exceptional healing capability of oral mucosa, most efforts are focused on protein coding genes. Little is known about the role of non-coding genes (e.g. microRNA) and their contribution to the enhanced wound healing in oral mucosa. We hypothesize that, when compared to skin, epithelial cells in oral mucosa are genetically programmed to more rapidly and appropriately respond to injury. We hypothesize that epithelial cells in oral mucosa are genetically programmed to more rapidly and appropriately respond to injury. We further hypothesize that site-specific microRNA regulators exist in the skin and oral mucosal epithelial cells, and that these microRNAs play an important role in the tissue specific response to injury. Two specific aims are proposed to test this hypothesis. Aim 1 will establish the dynamic microRNA profiles of epithelial cells from paired oral mucosal wounds and skin wounds, and will define the microRNA signature that is associated with enhanced wound healing in oral mucosa. Aim 2 will assess the functional contribution of microRNA to the epithelial component of wound healing, and will evaluate the feasibility of regulating wound healing outcomes (e.g., accelerating wound closure) by manipulating specific microRNAs in vivo. These studies are designed to provide novel information about how microRNAs contribute to the different healing dynamics in different tissues. This understudied area has great potential to suggest original therapeutic approaches for the repair and regeneration of tissues of the craniofacial complex, including skin and mucosa.